The flap endonuclease-1 mediated maturation of Okazaki fragments is critical for the cellular tolerance to remdesivir.

Remdesivir is a 1'-cyano-modified adenine nucleotide analog used for the treatment of COVID-19. Recently, the anti-carcinogenic effect of remdesivir has been also identified in human cancers. However, the impact of this drug and the mechanisms underlying the cellular tolerance to remdesivir have not been elucidated.

CTF18-RFC contributes to cellular tolerance against chain-terminating nucleoside analogs (CTNAs) in cooperation with proofreading exonuclease activity of DNA polymerase ε.

Chemotherapeutic nucleoside analogs, such as cytarabine (Ara-C), are incorporated into genomic DNA during replication. Incorporated Ara-CMP (Ara-cytidine monophosphate) serves as a chain terminator and inhibits DNA synthesis by replicative polymerase epsilon (Polε). The proofreading exonuclease activity of Polε removes the misincorporated Ara-CMP, thereby contributing to the cellular tolerance to Ara-C.